4.1. Therapeutic indications

Treatment of essential hypertension.

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg fixed dose combinations are indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg alone.

4.2. Posology and method of administration

Posology

Adults

The recommended dose of Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg or Olmesartan/Hydrochlorothiazide 40 mg/25 mg is 1 tablet per day.

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.

Olmesartan/Hydrochlorothiazide 40 mg /25 mg may be administered in patients whose blood pressure is not adequately controlled on Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg fixed dose combination.

For convenience, patients receiving olmesartan medoxomil and hydrochlorothiazide from separate tablets may be switched to Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg tablets containing the same component doses.

This medicine can be taken with or without food.

Elderly (age 65 years or over)

In elderly people the same dosage of the combination is recommended as for adults.

Blood pressure should be closely monitored.

Renal impairment

Olmesartan/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.3).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 ml/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group, and periodic monitoring is advised.

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see sections 4.3, 4.4, 5.2).

Hepatic impairment

Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg should be used with caution in patients with mild hepatic impairment (see sections 4.4, 5.2). Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment. <Product Name> 40 mg/12.5 mg and 40 mg/25 mg therefore should not be used in patients with moderate and severe hepatic impairment (see sections 4.3, 5.2), as well as in cholestasis and biliary obstruction (see section 4.3).

Paediatric population

The safety and efficacy of olmesartan/hydrochlorothiazide in children and adolescents below 18 years has not been established. No data are available.

Method of administration

Olmesartan/Hydrochlorothiazide is administered once daily, with or without food. The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

4.3. Contraindications

• Hypersensitivity to the active substances, to any of the excipients listed in section 6.1 or to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).

• Renal impairment (see sections 4.4 and 5.2).

• Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

• Moderate and severe hepatic impairment, cholestasis and biliary obstructive disorders (see section 5.2).

• 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6).

• The concomitant use of olmesartan medoxomil/hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4. Special warnings and precautions for use

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil/hydrochlorothiazide.

Other conditions with stimulation of the renin-angiotensin-aldosterone system

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin- aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin- angiotensin-aldosterone system.

Renal impairment and kidney transplantation

Olmesartan medoxomil/hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 ml/min) is 20 mg olmesartan medoxomil once daily. However, in such patients olmesartan medoxomil/hydrochlorothiazide 20 mg/12.5 mg and 20 mg/25 mg should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic- associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

Olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg is therefore contraindicated in all stages of renal impairment (see section 4.3).

There is no experience of the administration of olmesartan/hydrochlorothiazide in patients with a recent kidney transplantation.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment

There is currently no experience of olmesartan medoxomil in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the maximum dose is 20 mg olmesartan medoxomil.

Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Therefore the use of olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg in patients with moderate and severe hepatic impairment, cholestasis and biliary obstruction is contraindicated (see sections 4.3, 5.2). Care should be taken in patients with mild impairment (see section 4.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil/hydrochlorothiazide is not recommended in such patients.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of this medicine hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended.

Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e.g. heparin) should be co-administered cautiously with olmesartan medoxomil/hydrochlorothiazide (see section 4.5).

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium

As with other angiotensin II receptor antagonists, the coadministration of olmesartan medoxomil/hydrochlorothiazide and lithium is not recommended (see section 4.5).

Sprue-like enteropathy

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localised delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent aetiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Ethnic differences

As with all other angiotensin II receptor antagonist containing products, the blood pressure lowering effect of olmesartan medoxomil is somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Anti-doping test

Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

Intestinal angioedema:

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including olmesartan medoxomil/hydrochlorothiazide (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Olmesartan medoxomil/hydrochlorothiazide should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, this medicinal product should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Other

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

This medicinal product contains lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Potential interactions related to both olmesartan medoxomil and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of olmesartan medoxomil/hydrochlorothiazide and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products

NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists.

In some patients with compromised renal function (e.g. dehydrated patients or elderly people with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in elderly people. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Concomitant use to be taken into account

Amifostine

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents

The blood pressure lowering effect of olmesartan medoxomil/hydrochlorothiazide can be increased by concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers or aliskiren

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Medicinal products affecting potassium levels

Based on experience with the use of other medicinal products that affect the renin angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with olmesartan/hydrochlorothiazide, monitoring of potassium plasma levels is advised.

Bile acid sequestering agent colesevelam

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to hydrochlorothiazide

Concomitant use not recommended

Medicinal products affecting potassium levels

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended.

Concomitant use requiring caution

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis induced cardiac arrhythmias.

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when olmesartan/hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide).

• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Non-depolarising skeletal muscle relaxants (e.g. tubocurarine)

The effect of non-depolarising skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Antidiabetic medicinal products (oral agents and insulin)

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Metformin

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta-blockers and diazoxide

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline)

The effect of pressor amines may be decreased.

Medicinal products used in the treatment of gout (e.g. probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine

Thiazides may increase the risk of adverse effects caused by amantadine.

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Tetracyclines

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea.

This interaction is probably not applicable to doxycycline.

4.6. Fertility, pregnancy and lactation

Pregnancy

Given the effects of the individual components in this combination product on pregnancy, the use of olmesartan medoxomil/hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of olmesartan medoxomil/hydrochlorothiazide is contraindicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Olmesartan medoxomil

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3 “Preclinical safety data”).

Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breast-feeding

Olmesartan medoxomil

Because no information is available regarding the use of olmesartan/hydrochlorothiazide during breast-feeding, olmesartan medoxomil/hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production.

The use of olmesartan medoxomil/hydrochlorothiazide during breast-feeding is not recommended. If olmesartan medoxomil/hydrochlorothiazide is used during breast feeding, doses should be kept as low as possible.

4.7. Effects on ability to drive and use machines

Olmesartan medoxomil/hydrochlorothiazide can have minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.

4.8. Undesirable effects

The most commonly reported adverse reactions during treatment with olmesartan medoxomil/hydrochlorothiazide are headache (2.9 %), dizziness (1.9 %) and fatigue (1.0 %).

Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).

The safety of olmesartan medoxomil/hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg was investigated in clinical trials in 3,709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide.

Further adverse reactions reported with the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide in the lower dose strengths 20 mg/12.5 mg and 20 mg/25 mg may be potential adverse reactions with Olmesartan/Hydrochlorothiazide 40 mg/12.5 mg and 40 mg/25 mg.

Adverse reactions from olmesartan medoxomil/hydrochlorothiazide in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and hydrochlorothiazide based on the known safety profile of these substances.

The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

MedDRA

System Organ Class

Adverse reactions

Frequency

Olmesartan/HCTZ

Olmesartan

HCTZ

Infections and infestations

Sialadenitis

Rare

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Non-melanomic skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

Not known

Blood and lymphatic system disorders

Aplastic anaemia

Rare

Bone marrow depression

Rare

Haemolytic anaemia

Rare

Leukopenia

Rare

Neutropenia/Agranulocytosis

Rare

Thrombocytopenia

Uncommon

Rare

Immune system disorders

Anaphylactic reactions

Uncommon

Uncommon

Metabolism and nutrition disorders

Anorexia

Uncommon

Glycosuria

Common

Hypercalcaemia

Common

Hypercholesterolaemia

Uncommon

Very common

Hyperglycaemia

Common

Hyperkalaemia

Rare

Hypertriglyceridaemia

Uncommon

Common

Very common

Hyperuricaemia

Uncommon

Common

Very common

Hypochloraemia

Common

Hypochloraemic alkalosis

Very rare

Hypokalaemia

Common

Hypomagnesaemia

Common

Hyponatraemia

Common

Hyperamylasaemia

Common

Psychiatric disorders

Apathy

Rare

Depression

Rare

Restlessness

Rare

Sleep disturbance

Rare

Nervous system disorders

Confusional state

Common

Convulsions

Rare

Disturbances in consciousness (such as loss of consciousness)

Rare

Dizziness/light-headedness

Common

Common

Common

Headache

Common

Common

Rare

Loss of appetite

Uncommon

Paraesthesia

Rare

Postural dizziness

Uncommon

Somnolence

Uncommon

Syncope

Uncommon

Eye disorders

Lacrimation decreased

Rare

Transient blurred vision

Rare

Worsening of pre-existing myopia

Uncommon

Choridal effusion, acute myopia, acute angle-closure glaucoma

Not known

Xanthopsia

Rare

Ear and labyrinth disorders

Vertigo

Uncommon

Uncommon

Rare

Cardiac disorders

Angina pectoris

Uncommon

Cardiac arrhythmias

Rare

Palpitations

Uncommon

Vascular disorders

Embolism

Rare

Hypotension

Uncommon

Rare

Necrotising angiitis (vasculitis, cutaneous vasculitis)

Rare

Orthostatic hypotension

Uncommon

Uncommon

Thrombosis

Rare

Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome (ARDS) (see section 4.4)

Very rare

Bronchitis

Common

Cough

Uncommon

Common

Dyspnoea

Rare

Interstitial pneumonia

Rare

Pharyngitis

Common

Pulmonary oedema

Rare

Respiratory distress

Uncommon

Rhinitis

Common

Gastrointestinal disorders

Abdominal pain

Uncommon

Common

Common

Constipation

Common

Diarrhoea

Uncommon

Common

Common

Dyspepsia

Uncommon

Common

Gastric irritation

Common

Gastroenteritis

Common

Meteorism

Common

Nausea

Uncommon

Common

Common

Pancreatitis

Rare

Intestinal angioedema

Rare

Paralytic ileus

Very rare

Vomiting

Uncommon

Uncommon

Common

Sprue-like enteropathy (see section 4.4)

Very rare

Hepatobiliary disorders

Acute cholecystitis

Rare

Jaundice (intrahepatic cholestatic icterus)

Rare

Autoimmune hepatitis*

Not known

Skin and subcutaneous tissue disorders

Allergic dermatitis

Uncommon

Anaphylactic skin reactions

Rare

Angioneurotic oedema

Rare

Rare

Cutaneous lupus erythematosus-like reactions

Rare

Eczema

Uncommon

Erythema

Uncommon

Exanthem

Uncommon

Photosensitivity reactions

Uncommon

Pruritus

Uncommon

Uncommon

Purpura

Uncommon

Rash

Uncommon

Uncommon

Uncommon

Reactivation of cutaneous lupus erythematosus

Rare

Toxic epidermal necrolysis

Rare

Urticaria

Rare

Uncommon

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Uncommon

Arthritis

Common

Back pain

Uncommon

Common

Muscle spasm

Uncommon

Rare

Muscular weakness

Rare

Myalgia

Uncommon

Uncommon

Pain in extremity

Uncommon

Paresis

Rare

Skeletal pain

Common

Renal and urinary disorders

Acute renal failure

Rare

Rare

Haematuria

Uncommon

Common

Interstitial nephritis

Rare

Renal insufficiency

Rare

Renal dysfunction

Rare

Urinary tract infection

Common

Reproductive system and breast disorders

Erectile dysfunction

Uncommon

Uncommon

General disorders and administration site conditions

Asthenia

Common

Uncommon

Chest pain

Common

Common

Face oedema

Uncommon

Fatigue

Common

Common

Fever

Rare

Influenza-like symptoms

Common

Lethargy

Rare

Malaise

Rare

Uncommon

Pain

Common

Peripheral oedema

Common

Common

Weakness

Uncommon

Investigations

Alanine aminotransferase increased

Uncommon

Aspartate aminotransferase increased

Uncommon

Blood calcium increased

Uncommon

Blood creatinine increased

Uncommon

Rare

Common

Blood creatine phosphokinase increased

Common

Blood glucose increased

Uncommon

Blood haematocrit decreased

Rare

Blood haemoglobin decreased

Rare

Blood lipids increased

Uncommon

Blood potassium decreased

Uncommon

Blood potassium increased

Uncommon

Blood urea increased

Uncommon

Common

Common

Blood urea nitrogen increased

Rare

Blood uric acid increased

Rare

Gamma glutamyl transferase increased

Uncommon

Hepatic enzymes increased

Common

*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

No specific information is available on the effects or treatment of olmesartan/hydrochlorothiazide overdose. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

The most likely manifestations of olmesartan medoxomil overdose are expected to be hypotension and tachycardia; bradycardia might also occur. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.